Colloidal Aggregators in Biochemical SARS-CoV-2 Repurposing Screens

To fight COVID-19, much effort has been directed toward in vitro drug repurposing. Here, we investigate the impact of colloidal aggregation, a common screening artifact, in these repurposing campaigns. We tested 56 drugs reported as active in biochemical assays for aggregation by dynamic light scattering and by detergent-based enzyme counter screening; 19 formed colloids at concentrations similar to their literature IC₅₀'s, and another 14 were problematic. From a common repurposing library, we further selected another 15 drugs that had physical properties resembling known aggregators, finding that six aggregated at micromolar concentrations. This study suggests not only that many of the drugs repurposed for SARS-CoV-2 in biochemical assays are artifacts but that, more generally, at screening-relevant concentrations, even drugs can act artifactually via colloidal aggregation. Rapid detection of these artifacts will allow the community to focus on those molecules that genuinely have potential for treating COVID-19.